PgmNr Y3065: The NaCl-activated signaling network responsible for protein phosphorylation in yeast reveals potential decision points in the growth-versus-stress decision.

Authors:
M. MacGilvray 1 ; E. Shishkova 2 ; D. Chasman 3 ; J. Coon 2 ; A. Gasch 1


Institutes
1) Laboratory of Genetics, University of Wisconsin - Madison; 2) Department of Chemistry, University of Wisconsin - Madison; 3) Wisconsin Institute for Discovery, University of Wisconsin - Madison.


Keyword: Signal Transduction

Abstract:

Cells respond to stressful conditions using a complex, multi-faceted approach that includes changes in gene expression, protein abundance, and post-translational modification. Coupled to these changes is arrest of growth, suggesting that these are competing cellular processes. Although the affects of transcript changes in response to stress are well characterized in Saccharomyces cerevisiae, we have only a rudimentary understanding of the upstream regulatory network and post-translational protein modifications that regulate stress response. To gain a better understanding of the regulatory network that controls stress response, including how stress and growth response pathways are connected, we developed an experimental and computational workflow to infer stress-activated signaling networks using protein-protein interactions and phosphorylation changes. Using a integer linear programming approach, we combined high throughput protein interaction datasets with quantitative mass spectrometry performed on the lab strain, BY4741, and derivative mutants of the cell cycle protein Cdc14, the MAPK Hog1, and the phosphodiesterase Pde2, before and five minutes after NaCl exposure. The resulting network implicated new regulators in the yeast stress response, revealed a complex, hierarchical organization of kinases and phosphatases, and identified potential decision points in the growth-versus-stress decision. Interestingly, our network is enriched for yeast genes whose human orthologs are linked to diseases, such as cancer, that can be caused by defects in kinase regulation. Through identification of novel pathway and regulator connections, including those involved in stress response and growth, we will improve our understanding of both yeast physiology and human disease causing mechanisms.



Yeast Database Genetic Index
1. gene symbol: hog1; systematic name: YLR113W
2. gene symbol: pde2; systematic name: YOR360C
3. gene symbol: cdc14; systematic name: YFR028C